DESCRIPTION: The major objective of this new proposal is to elucidate the role of cullin-4A in tumor development. This proposal is based on the interesting preliminary observations by the PI on the binding of cullin-4A with damaged-DNA recognition factor (DDB) in cell culture studies. To examine the role of cullin-4A in tumor development, the PI has hypothesized several mechanistic possibilities that will explain how overexpression of cullin-4A leads to the development of malignant tumors. The proposed studies will establish, 1) how cullin-4A modulates the functions of DDB; 2) how cullin-4A target DDB and cullin-4A are functionally different from cullin-4B; and 3) whether cullin-4A would be the target of any oncogenic pathways or whether it would cooperate with other oncogenes to immortalize or transform cells in culture. Also, the PI will develop a transgenic mouse model that over expresses cullin-4A in keratinocytes, which would enable him to study the oncogenic function in vivo.